Depression remains a serious medical illness for over 10 million Americans annually. For a large percentage, the existing treatment options fail, and there are no current options for these individuals. Recently, the sedative/anesthetic ketamine has been discovered to possess activity in treatment-resistant depression. There remain, however, issues in its realization as an effective therapeutic option, including its addictive potential and psychotomimetic properties. Working with researchers at NIMH and the University of Maryland, we are exploring the potential that a naturally occurring metabolite of ketamine is the agent responsible for its anti-depressant activity. In a cadre of studies this key metabolite recapitulates all depression-relative phenotypes of ketamine without the addictive or psychotomimetic effects. Efforts to establish a pharmaceutical form of this agent for initiation of a clinical trial are currently underway.